Severe ocular hypotony [too low intraocular pressure (IOP)] can lead to blindness via Phthisis bulbi (shrunken, non-functional eyes). Currently, there are no effective treatments for hypotony. We recently showed that pharmacologic or genetic inhibition of bicarbonate-regulated soluble adenylyl cyclase (sAC) elevates IOP in wild type mice as well as in a mouse model of ocular hypotony. We have identified inhibitors of sAC in a small molecule screen, and we propose to develop these sAC inhibitors into first-in-class therapeutics for treatment of ocular hypotony. Our small molecule screen also identified the first known pharmacological tools for increasing sAC activity, and we propose to test whether they define lead compounds for a new therapeutic strategy for lowering IOP to treat glaucoma.